Levels of epitope presentation and CD4+ T cell responses in autoimmunity and in response to immunization

CD4+ T lymphocytes recognize peptides associated with MHC class II molecules on the surface of professional antigen presenting cells (APCs). These studies examine how the level of peptide presentation affects the CD4+ T cell response during autoimmune reactions, and after immunization with protein in adjuvant.; The number of peptide-MHC molecules required to delete T cells developing in the thymus is extremely low, occurring between 1 and 10 peptide-MHC molecules per APC. The number of complexes required to activate a naive CD4+ T cells requires significantly higher levels of presentation, occurring between 100–1,000 peptide-MHC molecules per APC. We have termed this difference in numbers of peptide-MHC molecules as a biochemical margin of safety, referring to the 100-fold higher levels of presentation that are required to activate a self reactive T cell that escapes negative selection. We describe a model in which self reactive T cells that are partially deleted in the thymus are able to cause diabetes when the HEL protein is expressed at high levels in the pancreas. We conclude that epitopes that are presented in limited numbers in the thymus, but in high numbers in a lymph node draining a peripheral organ, can lead to the escape of autoreactive T cells from the thymus and activation in the periphery leading to the development of autoimmunity.; In other studies we examine the T cell responses to four peptides presented from the model protein HEL after immunization with protein in adjuvant. The initial expectation was that the peptides presented at the highest levels would generate more T cells when antigen was limiting, or when costimulatory molecules were absent. The data demonstrate that this is not the case however, as similar proportions of T cells were observed to high and low abundance epitopes after immunizing mice with high and low amounts of antigen and after immunizing mice deficient for the costimulatory molecule CD40, and mice deficient for both B7-1 and B7-2. Furthermore, blocking the negative regulatory molecule CTLA-4 during priming did not affect T cell responses to high or low abundance epitopes. These studies demonstrate that T cell priming after immunization is an extremely efficient process, and the relative distribution of T cells responding to different epitopes is independent of the level of peptide-MHC presentation.